The immune system must achieve a balance between effective responses to eliminate pathogenic entities (e.g. in cancer), while maintaining tolerance to prevent autoimmune disease. T cells serve a critical role in maintaining a balance between suppression of immune function, and active immune rejection. T regulatory cells (Tregs) are characterized by the expression of CD25+, CD4+, FOXp3+ and glucocorticoid-induced tumor necrosis factor-related receptor (GITR). Tregs suppress pathological immune responses, and ultimately maintain immune homeostasis by way of regulating immunological self-tolerance. The presence of Tregs suppresses the activity of activated, effector T cells which are responsible for eliminating various pathological entities.
Human epithelial malignancies have been associated with the presence of increased amounts of Tregs both in the circulation and within the tumor itself. The increased presence of suppressive Tregs in cancer patients, results in a suppression of conventional T cells, including effector cells, which in turn leads to a downregulation in IFN-γ production. Reduction of the presence or the activity of Tregs in in vivo cancer animal models has resulted in an increase in the amounts and activity of effector T cells, which is often followed by a decrease in size of the tumor and or alleviation of other cancer symptoms.
T cell activation results in an upregulation of GITR levels in both Tregs and effector T cells. Manners of modulating the activity of GITR, such that the Tregs immune suppressing function is reduced, and the activity of effector T cells is increased is an ongoing area of intense study. The GITR ligand, GITR-L, is expressed in a variety of cells including dendritic cells, macrophages and B cells. Previous studies have shown an association between increased anti-tumor immune activity following administration of exogenous GITR-L, or by alternate means of antagonizing GITR, in cancer models.
Given the increased presence, and the role that Tregs have in cancer, further attention to modulating the activity and presence of Tregs, via GITR, is paramount in further understanding and, ultimately, in the treatment of cancer. Therefore, there exists an urgent need for agents that can specifically bind and modulate the binding of GITR with its ligand, GITR-L, as a means to promote effector T cell activity and, as a result, anti-tumor activity.